Systemic pan-AMPK activator MK-8722 improves glucose homeostasis but induces cardiac hypertrophy

Robert W Myers,Guillermo E Fernandez,Mark D Erion,Xiaodong Yang,Ku Lu,Liyang Wang,David E Kelley,James A Milligan,Franklin Liu,Hong-Ping Guan,Marie A Holahan,Stacey Conarello,Sandra C Souza,Effie Tozzo,Bindu Bennet,Xiaoda Niu,Cai Li,Marc M Kurtz,Wen Feng,Lisa Lafranco Scheuch,Douglas Wisniewski,Wei Zhu,Danqing Feng,Michelle Bunzel,Tesfaye Biftu,Rory J Rohm,Jinqi Liu,Ronald E Painter,Huaibing He,Juliann Ehrhart,Margaret Van Heek,Michael Klimas,Daniel Rubins,Iyassu K Sebhat,Hongwu Wang,Shiyao Xu,Ying Qian,Gaochao Zhou,George J Eiermann ,Nancy A Thornberry ,Ann E Weber ,Ying Liu ,D S Kemp ,A N Petrov ,Corin O Miller ,Dinko González Trotter ,S Prahalada ,Aimie M Ogawa ,María E Trujillo

doi:10.1126/science.aah5582

Abstract

5'-Adenosine monophosphate-activated protein kinase (AMPK) is a master regulator of energy homeostasis in eukaryotes. Despite three decades of investigation, the biological roles of AMPK and its potential as a drug target remain incompletely understood, largely because of a lack of optimized pharmacological tools. We developed MK-8722, a potent, direct, allosteric activator of all 12 mammalian AMPK complexes. In rodents and rhesus monkeys, MK-8722-mediated AMPK activation in skeletal muscle induced robust, durable, insulin-independent glucose uptake and glycogen synthesis, with resultant improvements in glycemia and no evidence of hypoglycemia. These effects translated across species, including diabetic rhesus monkeys, but manifested with concomitant cardiac hypertrophy and increased cardiac glycogen without apparent functional sequelae.

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